Bipolar II disorder (BD-II) is a subtype of bipolar disorder (BD) characterized as “recurrent episodes of depression and hypomania.” BD-II is often misdiagnosed because diagnoses are frequently made based on recollections of past hypomania when patients are having symptoms of depression. Therefore, BD-II is often ineffectively treated. Patients with BD-II have a greater risk of suicide, a prolonged clinical course, more mood episodes, more major and minor depressive episodes, and shorter inter-episode intervals, than do patients with bipolar I disorder (BD-I).
Patients with BD frequently have comorbid alcohol use disorders (AUDs), especially patients with BD-II. Irritable and hyperthymic temperaments might contribute to AUDs in BD-II patients. Comorbid AUDs in BD-II patients worsens the clinical presentation with higher rates of mixed episodes, rapid cycling and increased symptom severity. In addition, even in the inter-episode state, BD-II patients comorbid with AUDs performed poorly on verbal, visual, and working memory, psychomotor speed, and attention span tests than did BD-II patients without AUDs and super-normal healthy controls. Both BD and AUDs are neurodegenerative diseases likely to increase toxins and nerve damage in various brain areas; comorbid BD and AUDs might lead to detrimental effects. Alcohol dependence might be categorized into four subtypes: (a) simple, (b) anxiety-depression, (c) mixed (bipolar), and (d) antisocial subtypes with genetic variations in Han Chinese populations (Shan et al., Neuropsychological functions in Han Chinese patients in Taiwan with bipolar II disorder comorbid and not comorbid with alcohol abuse/alcohol dependence disorder. Prog Neuropsychopharmacol Biol Psychiatry, 35:131-136, 2011). Previous clinical experience shows that it is more difficult for BD patients with the mixed subtype to stop drinking than it is for those with the simple and anxiety-depression subtypes.
Memantine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. However, an alternative mechanism for memantine has been reported: memantine functions as an anti-inflammatory agent that downregulates the activity of microglia and upregulates astroglia-released neurotrophic factors, which is mechanistically remote from an NMDA receptor (Wu et. Al, Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation, Neuropsychopharmacology 34:2344-2357, 2009). Low-dose (0.02 mg/kg) memantine abolishes morphine-induced conditioned-place-preference behavior in rats because of its IL-6-modulating effect on the medial prefrontal cortex and IL-1β-modulating effect on the nucleus accumbens (Chen et al., Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats, Journal of neuroimmune pharmacology: the official journal of the Society on NeuroImmune Pharmacology, 7:444-453, 2012). In addition, add-on memantine in opioid-dependent patients undergoing methadone maintenance treatment not only significantly downregulates plasma tumor necrosis factor-α (TNF-α) levels and upregulates transforming growth factor-β1 (TGF-β1) levels, but also reduces the required methadone dose (Lee et al., Low-dose memantine attenuated methadone dose in opioid-dependent patients: a 12-week double-blind randomized controlled trial, Sic Rep 5:10140, 2015).